Preparation process of a menthol ointment

Abstract

The present invention discloses a preparation process of menthol ointment, belonging to the technical field of ointments. The process uses cyclodextrin modified by hydroxyethyl polymethacrylate and quaternary ammonium salt as a carrier to encapsulate menthol molecules, enhancing the stability of the menthol ointment. The addition of hydroxyethyl polymethacrylate can act as a thickening agent and a stabilizer, improving the physical stability of the ointment while forming hydrogen bond interactions with menthol molecules; the quaternary ammonium salt has broad-spectrum antibacterial activity, which can effectively inhibit the growth of bacteria, fungi and certain viruses, and the repulsion between cations further improves the dispersibility of cyclodextrin. This modified structure can prevent the volatilization of menthol, reduce losses, and also avoid the reaction of menthol with air and other substances, thereby improving the stability of menthol; it can control the release time, allowing the cooling sensation of menthol to be slowly and durably released during use, prolonging the use effect; it can mask the pungent odor, making the product more acceptable.

Description

Technical Field

[0001] The present invention belongs to the technical field of ointments, and particularly relates to a preparation process of menthol ointment. Background Art

[0002] In today's pharmaceutical field, there is a wide range of application demands for topical skin preparations. As the largest organ of the human body, the skin often faces various problems, such as mosquito bites, skin itching, minor sunburns, dry chapping, etc. Menthol ointment, as a classic topical skin preparation, has long been widely used. Menthol is extracted from the leaves and stems of mint and can be used as a flavoring agent in toothpaste, perfume, beverages, candies, etc. In medicine, it is used as a stimulant, acting on the skin or mucous membrane, having a cooling and antipruritic effect. Orally, it can be used as an antispasmodic for headache and nasal, pharyngeal, and laryngeal inflammations, etc. Menthol can selectively stimulate the cold receptors of the human skin or mucous membrane, generating a cold sensation reflex and a cold feeling, causing vasoconstriction of the skin and mucous membrane blood vessels (in fact, the skin remains normal). In addition, it can also cause vasoconstriction of the blood vessels in deep tissues, thus producing a therapeutic effect. When used externally, it can reduce inflammation, relieve pain, stop itching, promote blood circulation, and reduce swelling, etc.

[0003] However, the early preparation process of menthol ointment was relatively crude, mostly using a simple mixing method, directly stirring menthol with petrolatum or other matrices, which led to uneven dispersion of menthol, poor stability of the ointment, and greatly reduced drug efficacy.

[0004] There are many methods to stabilize ointments, including methods of using carriers to encapsulate drugs, such as nanoparticle encapsulation, microemulsion encapsulation, and liposome encapsulation. The above methods may all have different degrees of disadvantages. For example, in the method of nanoparticle encapsulation, the surface properties of the nanoparticles may affect their interaction with biological membranes, thereby affecting drug absorption and distribution; in the method of microemulsion encapsulation, surfactants and co-surfactants may cause irritation to the skin; the liposome encapsulation preparation process is complex and costly, and in addition, the physical stability of liposomes is poor, and they are prone to aggregation, fusion, and leakage during storage and use. Therefore, there is still a need to develop a preparation process of menthol ointment with good dispersion and stability. Summary of the Invention

[0005] In order to overcome the above deficiencies of the prior art, the present invention provides a preparation process of menthol ointment, using cyclodextrin modified by poly (2-hydroxyethyl methacrylate) and quaternary ammonium salt as a carrier to encapsulate menthol molecules, enhancing the stability of menthol ointment to solve the above problems.

[0006] The technical solution to achieve the object of the present invention is as follows:

[0007] A preparation method of menthol ointment, comprising the following steps:

[0008] S1. Weigh 282 - 300 parts of the mixed solution of glycerol and deionized water and 100 - 108 parts of lanolin, place them in a beaker, heat to 40 - 60 °C and stir evenly.

[0009] S2. Then add 10 - 12 parts of menthol encapsulated by modified cyclodextrin and stir evenly.

[0010] S3. Cool down, discharge the material, and check whether the appearance, texture, and smell of the menthol ointment meet the requirements.

[0011] The preparation method of the menthol encapsulated by modified cyclodextrin is as follows:

[0012] Disperse 1 part of menthol and 3 - 6 parts of modified cyclodextrin in the mixed solution of water and ethanol, stir until evenly dispersed, and then perform freeze-drying to obtain the menthol encapsulated by modified cyclodextrin.

[0013] The menthol encapsulated by modified cyclodextrin is obtained by polymerizing and grafting cyclodextrin with 2-hydroxyethyl methacrylate and methacryloyloxyethyl trimethyl ammonium chloride.

[0014] Preferably, the preparation method of the modified cyclodextrin is as follows:

[0015] 1) Mix 4 - 6 parts of cyclodextrin, 8 - 10 parts of triethylamine and 20 - 25 parts of toluene. Under vigorous stirring at 0 °C, gradually add 6 - 8 parts of 3-chloropropionyl chloride. Heat the reaction to room temperature and stir overnight. Wash with cold water and brine, add solid sodium sulfate for drying, and then remove the solvent under reduced pressure to obtain product A.

[0016] 2) Disperse 1 part of the product A obtained in step 1) in 25 - 30 parts of anhydrous tetrahydrofuran. After ultrasonic treatment for 20 - 30 min, transfer it to a reaction kettle. Add 10 - 15 parts of 2-hydroxyethyl methacrylate, 1 - 2 parts of methacryloyloxyethyl trimethyl ammonium chloride and 0.01 - 0.03 parts of cuprous bromide. Perform freeze-thaw degassing three times. Under an inert atmosphere, add 0.15 - 0.22 parts of N,N,Nˋ,Nˋ,Nˋˋ-pentamethyldiethylenetriamine ligand, heat to 50 - 60 °C and stir for 8 - 16 h; introduce oxygen to terminate the polymerization reaction; perform rotary evaporation and concentration, filtration, column chromatography purification, and dry the modified cyclodextrin.

[0017] Preferably, the optimal mass ratio of the mixed solution of glycerol and deionized water is 1:2 - 3:1.

[0018] Preferably, the gradual addition of 3-chloropropionyl chloride means adding 3-chloropropionyl chloride completely within 10 - 20 min.

[0019] Preferably, the inert atmosphere is argon or nitrogen.

[0020] Preferably, the cyclodextrin is one or more of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0021] Another object of the present invention is to protect a menthol ointment prepared by the above-mentioned preparation method of the menthol ointment.

[0022] Beneficial effects

[0023] The present invention includes the following beneficial effects:

[0024] 1. The addition of poly(2-hydroxyethyl methacrylate) can act as a thickening agent and a stabilizer, improving the physical stability of the ointment and preventing the components from stratifying or separating; at the same time, the addition of poly(2-hydroxyethyl methacrylate) can form hydrogen bonds with menthol molecules outside the cyclodextrin, achieving a sustained-release effect of gradually releasing menthol molecules.

[0025] 2. Quaternary ammonium salts have broad-spectrum antibacterial activity and can effectively inhibit the growth of bacteria, fungi, and certain viruses.

[0026] 3. The menthol molecules encapsulated by the modified cyclodextrin are stably present, can be evenly dispersed in the ointment, improving the quality stability of the product and the consistency of the efficacy. This structure can prevent the volatilization of menthol, reduce losses, and also avoid the reaction of menthol with air and other substances, thereby improving the stability of menthol; it can control the release time, allowing the cooling sensation of menthol to be slowly and continuously released during use, prolonging the use effect; and it can mask the pungent odor, making the product more acceptable.

[0027] 4. The menthol ointment prepared by this process has a delicate and uniform texture, is easy to apply, and has good skin-friendly properties. Description of the drawings

[0028] Figure 1 is the process of cyclodextrin modification.

[0029] Figure 2 are the infrared spectra of cyclodextrin and modified cyclodextrin. Detailed implementation manners

[0030] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0031] In the embodiments, the experimental methods used are all conventional methods unless otherwise specified, and the materials, reagents, etc. used can be obtained from commercial channels unless otherwise specified.

[0032] The raw materials and equipment used in the examples and comparative examples are described as follows:

[0033] Menthol: Product number BD 137401, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0034] γ-Cyclodextrin: Product number BD131847, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0035] 3-Chloropropionyl chloride: Product number BD41878, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0036] Methacryloyloxyethyltrimethylammonium chloride: Product number BD137604, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0037] 2-Hydroxyethyl methacrylate: Product number BD22916, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0038] N,N,Nˋ,Nˋ,Nˋˋ-Pentamethyldiethylenetriamine: Product number BD52200, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0039] Lanolin: Product number JX443963, purchased from Anhui Zesheng Technology Co., Ltd.;

[0040] Glycerol: Product number BD132150, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

[0041] Ethanol: Product number A040857, purchased from Anhui Zesheng Technology Co., Ltd.;

[0042] Acetonitrile: Product number A011968, purchased from Anhui Zesheng Technology Co., Ltd.;

[0043] Phosphoric acid: Product number M0113801, purchased from Anhui Zesheng Technology Co., Ltd.;

[0044] Bama pig skin for 2-3 month-old experimental use: purchased from Linxi County Jingde Agricultural Products Sales Co., Ltd.;

[0045] Modified cyclodextrin: self-made.

[0046] The following are the test methods for the performance parameters involved in the present invention:

[0047] (1) Parameters for high performance liquid chromatography detection: Instrument: ThermoFisherUV3000; Chromatographic column: Core-shell ascentisExpress C 18 , 5μm, 4.6x 150mm, Mobile phase: 0.1% phosphoric acid solution - acetonitrile (60:40) by volume concentration, Column temperature 30°C; Flow rate 1.0 mL / min; Detection wavelength 254 nm.

[0048] (2) Sustained-release effect test: To study the sustained-release effect of menthol and ensure the conditions simulating human skin, pig skin was used to simulate human skin to observe its sustained-release effect. The test method is as follows:

[0049] Prepare pig skins labeled 1 to 6 with a size of 4x4 cm 2 Apply the ointments of Examples 1 to 6 with thicknesses of 0.5, 0.7, and 1.0 mm respectively, and keep the temperature at 36.8 - 37.1 °C; use high-performance liquid chromatography to test the sustained-release effect of the three thicknesses of ointments in each example every 2 h for a total of 8 h, and make Table 3.

[0050] (3) Antibacterial effect test: Detection method: Select Escherichia coli and Staphylococcus aureus, and refer to Appendix C4 of GB159779 - 2002 for antibacterial experiments. The specific results are shown in Table 4.

[0051] The present invention will be further described below in conjunction with the embodiments.

[0052] Modified cyclodextrin 1

[0053] 1) After mixing 4 parts of cyclodextrin, 10 parts of triethylamine and 25 parts of toluene, 8 parts of 3-chloropropionyl chloride were gradually added under violent stirring at 0 °C. The reaction was heated to room temperature and stirred overnight, washed with cold water and brine, dried by adding solid sodium sulfate, and the solvent was removed under reduced pressure to obtain product A;

[0054] 2) Disperse 1 part of the product A obtained in step S1 in 30 parts of anhydrous tetrahydrofuran, ultrasonicate for 20 min, transfer to a reaction kettle, add 15 parts of 2-hydroxyethyl methacrylate, 2 parts of methacryloyloxyethyl trimethylammonium chloride and 0.03 parts of cuprous bromide, freeze-thaw and degas three times. Under an inert atmosphere, add 0.15 - 0.22 parts of N,N,N`,N`,N``-pentamethyldiethylenetriamine ligand, heat to 60 °C and stir for 16 h; introduce oxygen to terminate the polymerization reaction; rotary evaporate and concentrate, filter, purify by column chromatography, and dry the modified cyclodextrin.

[0055] Modified cyclodextrin 2

[0056] Compared with the preparation method of modified cyclodextrin 1, the difference is that 2 parts of methacryloyloxyethyl trimethylammonium chloride in step 2) are replaced by 2 parts of 2-hydroxyethyl methacrylate.

[0057] The preparation method of menthol encapsulated by modified cyclodextrin is as follows: Mix menthol, ethanol and deionized water, add modified cyclodextrin or cyclodextrin, and freeze-dry to obtain menthol encapsulated by modified cyclodextrin. Table 1 shows Formulas 1 - 8 for preparing menthol encapsulated by cyclodextrin. The menthol encapsulated by modified cyclodextrin is obtained by polymerizing and grafting cyclodextrin with 2-hydroxyethyl methacrylate and methacryloyloxyethyl trimethylammonium chloride.

[0058] Table 1 Cyclodextrin-coated menthol formula 1-8 (g)

[0059]

[0060] The preparation method of menthol ointment is as follows:

[0061] Weigh the modified cyclodextrin-coated menthol, a mixed solution of glycerol and deionized water, and lanolin. Place the 1:1 mixed solution of glycerol and deionized water and lanolin in a beaker, heat, and stir evenly. Add the modified cyclodextrin-coated menthol to the mixture and stir evenly. Cool and discharge the mixture, and inspect the mint ointment to ensure that its appearance, texture, and odor meet the requirements. Table 2 shows the formulations for Examples 1-4 and Comparative Examples 1-4.

[0062] Table 2 Menthol ointment Examples 1 to 4, Comparative Examples 1 to 4 (g)

[0063]

[0064] Stability testing

[0065] In order to study the sustained-release effect of menthol and ensure the conditions of simulating human skin, pig skin was used to simulate human skin and observe its sustained-release effect.

[0066] The menthol ointments of Examples 1 to 4 and Comparative Examples 1 to 4 were applied to the skin layer side of the pigskin;

[0067] The temperature of the pigskin test was 36.8-37.1°C;

[0068] The pigskin is the skin of 2-3 month old Bama Xiang pigs for testing;

[0069] Table 3 Cumulative release rate of menthol ointment in Examples 1 to 4 and Comparative Examples 1 to 4

[0070]

[0071]

[0072] As can be seen from Table 3, when the ointment is applied at a thickness of 0.5 to 0.7 mm, it has a better sustained-release effect.

[0073] Antibacterial effect test of the ointment of the present invention

[0074] Table 4 Antibacterial effects of Examples 1 to 4 and Comparative Examples 1 to 4

[0075] Inhibitory rate against Escherichia coli (%) Inhibitory rate against Staphylococcus aureus (%) Example 1 87.1 79.8 Example 2 89.9 81.6 Example 3 92.2 83.4 Example 4 94.6 85.1 Comparative Example 1 49.9 49.2 Comparative Example 2 98.9 97.2 Comparative Example 3 50.2 49.5 Comparative Example 4 50.1 49.1

[0076] As can be seen from the above table, the ointment provided by the present invention has an obvious antibacterial effect and can effectively prevent skin infections caused by Staphylococcus aureus and Escherichia coli.

[0077] From the above experiments, it can be known that for Examples 1 to 4, the sustained-release effect increases successively, and the antibacterial effect increases successively; for Comparative Example 1, the sustained-release effect and antibacterial effect are the worst; for Comparative Example 2, the sustained-release effect is too strong and the release amount is too small; the sustained-release effect of Comparative Example 3 is slightly better than that of Example 2, but the antibacterial effect is poor; Comparative Example 4 has a certain sustained-release effect, but the antibacterial effect is poor; the results show that the addition of hydroxyethyl polymethacrylate in the modified cyclodextrin can form hydrogen bonds between the outside of the cyclodextrin and the menthol molecules to achieve the sustained-release effect of gradually releasing menthol molecules; the addition of quaternary ammonium salts can effectively inhibit the growth of bacteria.

[0078] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific embodiments described. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principle and practical application of the present invention, so that those skilled in the art can understand and utilize the present invention well. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. A preparation method of menthol ointment, characterized in that, It includes the following steps: S1. Weigh 282 - 300 parts of the mixed solution of glycerol and deionized water and 100 - 108 parts of lanolin, mix and heat them to 40 - 60 °C and stir evenly; S2. Then add 10 - 12 parts of menthol encapsulated by modified cyclodextrin and stir evenly; S3. Cool and discharge, and check whether the appearance, texture and smell of the menthol ointment meet the requirements; The preparation method of the menthol encapsulated by modified cyclodextrin is as follows: Disperse 1 part of menthol and 3 - 6 parts of modified cyclodextrin in the mixed solution of water and ethanol, stir until evenly dispersed, and then freeze-dry to obtain the menthol encapsulated by modified cyclodextrin; The menthol encapsulated by modified cyclodextrin is obtained by grafting cyclodextrin with the copolymer of 2-hydroxyethyl methacrylate and methacryloyloxyethyl trimethyl ammonium chloride; The preparation method of the modified cyclodextrin is as follows: 1) Mix 4 - 6 parts of cyclodextrin, 8 - 10 parts of triethylamine and 20 - 25 parts of toluene, and gradually add 6 - 8 parts of 3-chloropropionyl chloride under violent stirring at 0 °C. Heat the reaction to room temperature and stir overnight. Wash with cold water and brine, add solid sodium sulfate for drying, and then remove the solvent under reduced pressure to obtain product A; 2) Disperse 1 part of product A obtained in step 1) in 25 - 30 parts of anhydrous tetrahydrofuran, ultrasonicate for 20 - 30 min, then transfer to a reaction kettle, add 10 - 15 parts of 2-hydroxyethyl methacrylate, 1 - 2 parts of methacryloyloxyethyl trimethyl ammonium chloride and 0.01 - 0.03 parts of cuprous bromide, freeze-thaw and degas three times. Under an inert atmosphere, add 0.15 - 0.22 parts of N,N,N`,N`,N``-pentamethyldiethylenetriamine ligand, heat to 50 - 60 °C and stir for 8 - 16 h; Pass in oxygen to terminate the polymerization reaction, rotary evaporate and concentrate, filter, purify by column chromatography, and dry the modified cyclodextrin.

2. The preparation method of the menthol ointment according to claim 1, characterized in that, The mass ratio of the mixed solution of glycerol and deionized water is 1:2 - 3:

1.

3. The preparation method of the menthol ointment according to claim 1, characterized in that, The volume ratio of the mixed solution of water and ethanol is 1:1 - 1:2; The mass of the mixed solution of water and ethanol is 40 - 50 parts.

4. The preparation method of the menthol ointment according to claim 1, characterized in that, The gradual addition of 3-chloropropionyl chloride means adding 3-chloropropionamide completely within 10 - 20 min.

5. The preparation method of the menthol ointment according to claim 1, characterized in that, The inert atmosphere is argon or nitrogen.

6. The preparation method of the menthol ointment according to claim 1, wherein, The cyclodextrin is one or several of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin.

7. A menthol ointment, characterized in that, Prepared by the preparation method of the menthol ointment according to any one of claims 1 - 6.

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